Rapamycin is a macrocyclic triene compound that was initially extracted from a streptomycete (Streptomyces hygroscopicus) isolated from a soil sample from Easter Island (Vezina et al., J. Antibiot. 28:721 (1975); U.S. Pat. Nos. 3,929,992; 3,993,749). Rapamycin has the structure depicted in Formula I:
Originally described for use as an antifungal agent (U.S. Pat. No. 3,929,992), it has subsequently found to be an effective agent for other conditions and disorders, including use in the treatment of cancer and tumors (U.S. Pat. No. 4,885,171), use for the prevention of experimental immunopathies (experimental allergic encephalitis and adjuvant arthritis; Martel, R., Can. J. Physiol., 55:48 (1977)), inhibition of transplant rejection (U.S. Pat. No. 5,100,899), and inhibition of smooth muscle cell proliferation (Morris, R., J. Heart Lung Transplant, 11 (pt. 2) (1992)).
The numbering convention for rapamycin has been recently changed, and under the revised Chemical Abstracts nomenclature, what was formerly the 40-position is now the 42-position and the former 28-position is now the 31-position.
The utility of the compound as a pharmaceutical drug has been restricted by its very low and variable bioavailability and its high toxicity. Also, rapamycin is only very slightly soluble in water, i.e., 20 micrograms per milliliter, making it difficult to formulate into stable compositions suitable for in vivo delivery. To overcome these problems, prodrugs and derivatives of the compound have been synthesized. Water soluble prodrugs prepared by derivatizing rapamycin positions 31 and 42 (formerly positions 28 and 40) of the rapamycin structure to form glycinate, propionate, and pyrrolidino butyrate prodrugs have been described (U.S. Pat. No. 4,650,803). The numerous derivatives of rapamycin described in the art include monoacyl and diacyl derivatives (U.S. Pat. No. 4,316,885), acetal derivatives (U.S. Pat. No. 5,151,413), silly ethers (U.S. Pat. No. 5,120,842), hydroxyesters (U.S. Pat. No. 5,362,718), as well as alkyl, aryl, alkenyl, and alkynyl derivatives (U.S. Pat. Nos. 5,665,772; 5,258,389; 6,384,046; WO 97/35575).
One of the shortcomings of many of the prodrugs and derivatives of rapamycin is the complicated synthesis involved in preparing the prodrug or derivative, where additional synthetic steps are required to protect and deprotect certain positions. Also, care must be taken in designing prodrugs and derivatives to preserve activity of the compound and to sterically hinder positions necessary for protein binding or other cellular interactions. Derivatives having a shorter overall chain length and/or overall steric bulk (volume) in the chemical moiety attached to the compound are less likely to produce steric hindrance of binding sites. It would be desirable to design a derivative that has a shorter chain length or smaller size in the attached moiety.
One of the recent therapeutic uses of rapamycin and its derivatives has been treatment of restenosis. Restenosis after percutaneous transluminal coronary angioplasty (PTCA) remains one of its major limitations (Hamon, M. et al., Drug Therapy, 4:291–301 (1998)). The occurrence of restenosis after initial PTCA is between 30 and 50%, despite initial success (Bauters, C. et al., Am. Coll. Cardiol., 20:845–848 (1992); Bauters C. et al., Eur. Heart J., 16:33–48 (1995)). Restenosis after PTCA is thought to be a two component process of both intimal hyperplasia and vascular remodeling, the former coming initially, the latter occurring later in the process (Hoffman, R. et al., Circulation, 94:1247–1254 (1996); Oesterle, S. et al., Am. Heart J., 136:578–599 (1998)).
One strategy to eliminate or reduce restenosis is to limit the process of vascular remodeling. This can be accomplished by placing a stent in the lumen of the vessel after PTCA. Coronary stents are small metal tubular implants that are being extensively used to prevent acute reclosure or collapse of vessels following angioplasty. Currently, stents are routinely placed in 70 to 80% of all interventional cases.
In many cases this strategy works, however, the problem of restenosis is yet to be fully understood or conquered (Hamon, M. et al., Drug Therapy, 4:291–301 (1998); Oesterle, S. et al., Am. Heart J., 136:578–599 (1998)) The injury caused by angioplasty and stent placement often causes excessive healing response, including thrombosis and rapid cell proliferation inside the stent, leading to eventual reclosure of the vascular channel. There remains a need to solve the eventual renarrowing of the lumen inside the stent (i.e. restenosis) after angioplasty and stent placement experienced by many patients.